Project Summary Current antiretroviral (ARV) medications for HIV treatment and prevention require lifelong daily dosing, which can lead to reduced patient adherence due to pill fatigue, increasing the likelihood for treatment failure. Long-acting (LA) ARVs would allow less frequent administration, improving adherence. Despite success in the development of LA formulations for the non-nucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine and the integrase inhibitor cabotegravir, the nanomilling technologies used to produce them are incompatible with the nucleos(t)ide reverse transcriptase inhibitors (NRTIs) due to their high water solubility. Most current ARV combination therapies include administration of the NRTIs. Thus, in order to produce a complete LA dosing regimen, LA formulations of NRTIs are required. To enable the production of hydrophobic solid drug nanoparticles (SDNs), we propose the design, synthesis, and evaluation of a series of tunable emtricitabine (FTC) prodrugs that mask key hydrophilic groups and make these drugs compatible with SDN formulation approaches. Prodrug activation kinetics will be measured under a variety of physiologically relevant conditions to mimic those encountered by the complete regimen administered via intramuscular depot. In addition, prodrugs will be analyzed for lipophilicity and antiviral activity in cases where it is likely prodrugs will reach and undergo activation in target cells. The most promising candidates will be used to generate SDNs. The pharmacokinetic and efficacy benefits of these formulations will be tested with in vitro and in vivo model systems, guided by in silico physiologically-based pharmacokinetic modeling in collaboration with the University of Liverpool. Overall, this research is expected to accelerate the development of complete LA-ARV regimens to significantly improve adherence.